Promising Alzheimer’s therapy and related drugs shrink brains | Science

A class of Alzheimer’s drugs that aims to slow cognitive decline, including the antibody lecanemab that was granted accelerated approval in the United States in January, can cause brain shrinkage, researchers report in a new analysis. Although scientists and drug developers have documented this loss of brain volume in clinical trial participants for years, the scientific review, published yesterday in Neurology, is the first to look at data across numerous studies. It also links the brain shrinkage to a better known side effect of the drugs, brain swelling, which often presents without symptoms.

“We don’t fully know what these changes might imply,” says Jonathan Jackson, a cognitive neuroscientist at Massachusetts General Hospital. But, “These data are extremely concerning, and it’s likely these changes are detrimental.”

The analysis, which found that trial participants taking these Alzheimer’s drugs often developed more brain shrinkage than when they were on a placebo, alarmed Scott Ayton, a neuroscientist at the Florey Institute of Neuroscience and Mental Health in Melbourne, Australia, who led the work. “We’re talking about the possibility of brain damage” from treatment, says Ayton, who was invited by Eisai to join an advisory board on lecanemab’s rollout in Australia if the drug is approved there. “I find it very peculiar that these data, which are very important, have been completely ignored by the field.”

A spokesperson for Eisai suggested there are benign theories for the brain shrinkage, too. The company said that although participants in its pivotal trial did experience “greater cortical volume loss on lecanemab relative to placebo,” those reductions may be due to antibody clearing the protein beta amyloid from the brain, and reducing inflammation.

But that’s sheer speculation, some scientists worry. “We don’t know what it means” that more brain shrinkage occurs in treated participants than in people on placebo, says Lon Schneider, director of the California Alzheimer’s Disease Center at the Keck School of Medicine of the University of Southern California. “When we see volume loss on MRI, we tend to think that’s not good,” Schneider continues. It’s crucial to “try to seriously understand this.”

Ayton and two colleagues identified 31 published clinical trials of so-called antiamyloid Alzheimer’s drugs. All aim to eliminate beta amyloid, whose buildup many consider a driver of the disease. The drugs fell into two categories. One, secretase inhibitors, are traditional small-molecule drugs that target an enzyme that produces beta amyloid from a larger protein. These compounds have largely been abandoned because they didn’t pan out in trials. The second category included monoclonal antibodies like lecanemab that directly target various forms of beta amyloid. Another antiamyloid antibody in the analysis, aducanumab, was approved in 2021 amid much controversy, and still others are in trials. Sixteen of the 31 trials Ayton and his colleagues analyzed involved these lab-generated immune proteins.

Alzheimer’s disease frequently causes the brain to shrink as the illness progresses. But the researchers found both types of antiamyloid drugs generally caused clinical trial participants to lose more brain volume than what was seen in Alzheimer’s patients on a placebo. Lecanemab and another antibody, donanemab, made by Eli Lilly and Company and currently in late-stage trials, both “accelerated whole brain volume loss,” Ayton and colleagues write. People in two large lecanemab trials on the highest drug dose—which is the one the U.S. Food and Drug Administration (FDA) approved—recorded, on average, a 28% brain volume loss relative to placebo after about 18 months. This translated to a loss of an extra 5.2 milliliters (mL) in brain matter.

The authors also reported that the antiamyloid antibodies—but not the secretase inhibitors—led to an increase in the size of brain ventricles, indicating they were filling with extra fluid. This can happen when nearby brain tissue atrophies. People taking the now-approved dose of lecanemab had on average a 36% increase in the size of their brain ventricles compared with placebo—or an additional 1.9 mL.

Ayton’s group then studied whether a type of brain swelling and bleeding called amyloid-related imaging abnormalities (ARIA), a well-documented side effect of the antibodies, was associated with the other brain changes. ARIA occurred in 21% of the 898 people taking lecanemab in Eisai’s pivotal trial (as well as 9% on a placebo); most had no symptoms, but some did become severely ill and at least two died after extensive brain swelling and bleeding. Ayton and his colleagues found the experimental therapies with a higher rate of ARIA also generated a bigger average increase in the size of the ventricles.

“I was just shocked when we put these data together,” Ayton says. To him, there’s a logic behind this, though the connections haven’t been proved. ARIA shows up on brain scans as inflammation, and generally, “it’s not controversial that neuroinflammation would lead to neurodegeneration.” It’s possible, he theorizes, that patients who develop ARIA—which tends to happen early in treatment—may later develop brain volume loss and ventricles that take on more fluid.

Last year, Eisai’s pivotal trial of lecanemab in 1795 early Alzheimer’s patients revealed that the antibody slowed the rate of cognitive decline by 27% after 18 months compared with people on a placebo. Alzheimer’s experts agreed the benefit was modest, but many celebrated the results because it’s been so difficult to find drugs that stall the devastating loss of cognition.

FDA officials who approved Eisai’s application for lecanemab noted the brain volume changes. Like the company, though, they weren’t unduly concerned. A lead FDA reviewer “questions the clinical relevance of the changes to whole brain volume and total ventricular volume,” FDA wrote in its summary review of the drug, in part because the drug met its goal of slowing cognitive decline.

But researchers say the picture could be a lot more complicated. The publicly available information on brain volume loss and increase in ventricle size are averages across a trial population, and therefore make it hard to glean whether some people have more brain changes and how they fare. As Madhav Thambisetty, a neurologist at Johns Hopkins University and chief of the clinical and translational neuroscience section at the National Institute on Aging, says, “The published results do not provide any information on whether brain volume loss and increase in ventricular volume are associated with worsening clinical and cognitive outcomes” in individual patients. The “incomplete reporting of results … is very concerning to me.”

Ayton shares the sentiment. “The lack of information increases my worry,” he says, calling on companies, including Eisai, and drug regulators to examine this issue and share additional information from the trials. “You have more data—tell us why we shouldn’t be concerned.”

FDA is planning an advisory committee meeting by July to consider whether to grant lecanemab full approval.

A class of Alzheimer’s drugs that aims to slow cognitive decline, including the antibody lecanemab that was granted accelerated approval in the United States in January, can cause brain shrinkage, researchers report in a new analysis. Although scientists and drug developers have documented this loss of brain volume in clinical trial participants for years, the scientific review, published yesterday in Neurology, is the first to look at data across numerous studies. It also links the brain shrinkage to a better known side effect of the drugs, brain swelling, which often presents without symptoms.

“We don’t fully know what these changes might imply,” says Jonathan Jackson, a cognitive neuroscientist at Massachusetts General Hospital. But, “These data are extremely concerning, and it’s likely these changes are detrimental.”

The analysis, which found that trial participants taking these Alzheimer’s drugs often developed more brain shrinkage than when they were on a placebo, alarmed Scott Ayton, a neuroscientist at the Florey Institute of Neuroscience and Mental Health in Melbourne, Australia, who led the work. “We’re talking about the possibility of brain damage” from treatment, says Ayton, who was invited by Eisai to join an advisory board on lecanemab’s rollout in Australia if the drug is approved there. “I find it very peculiar that these data, which are very important, have been completely ignored by the field.”

A spokesperson for Eisai suggested there are benign theories for the brain shrinkage, too. The company said that although participants in its pivotal trial did experience “greater cortical volume loss on lecanemab relative to placebo,” those reductions may be due to antibody clearing the protein beta amyloid from the brain, and reducing inflammation.

But that’s sheer speculation, some scientists worry. “We don’t know what it means” that more brain shrinkage occurs in treated participants than in people on placebo, says Lon Schneider, director of the California Alzheimer’s Disease Center at the Keck School of Medicine of the University of Southern California. “When we see volume loss on MRI, we tend to think that’s not good,” Schneider continues. It’s crucial to “try to seriously understand this.”

Ayton and two colleagues identified 31 published clinical trials of so-called antiamyloid Alzheimer’s drugs. All aim to eliminate beta amyloid, whose buildup many consider a driver of the disease. The drugs fell into two categories. One, secretase inhibitors, are traditional small-molecule drugs that target an enzyme that produces beta amyloid from a larger protein. These compounds have largely been abandoned because they didn’t pan out in trials. The second category included monoclonal antibodies like lecanemab that directly target various forms of beta amyloid. Another antiamyloid antibody in the analysis, aducanumab, was approved in 2021 amid much controversy, and still others are in trials. Sixteen of the 31 trials Ayton and his colleagues analyzed involved these lab-generated immune proteins.

Alzheimer’s disease frequently causes the brain to shrink as the illness progresses. But the researchers found both types of antiamyloid drugs generally caused clinical trial participants to lose more brain volume than what was seen in Alzheimer’s patients on a placebo. Lecanemab and another antibody, donanemab, made by Eli Lilly and Company and currently in late-stage trials, both “accelerated whole brain volume loss,” Ayton and colleagues write. People in two large lecanemab trials on the highest drug dose—which is the one the U.S. Food and Drug Administration (FDA) approved—recorded, on average, a 28% brain volume loss relative to placebo after about 18 months. This translated to a loss of an extra 5.2 milliliters (mL) in brain matter.

The authors also reported that the antiamyloid antibodies—but not the secretase inhibitors—led to an increase in the size of brain ventricles, indicating they were filling with extra fluid. This can happen when nearby brain tissue atrophies. People taking the now-approved dose of lecanemab had on average a 36% increase in the size of their brain ventricles compared with placebo—or an additional 1.9 mL.

Ayton’s group then studied whether a type of brain swelling and bleeding called amyloid-related imaging abnormalities (ARIA), a well-documented side effect of the antibodies, was associated with the other brain changes. ARIA occurred in 21% of the 898 people taking lecanemab in Eisai’s pivotal trial (as well as 9% on a placebo); most had no symptoms, but some did become severely ill and at least two died after extensive brain swelling and bleeding. Ayton and his colleagues found the experimental therapies with a higher rate of ARIA also generated a bigger average increase in the size of the ventricles.

“I was just shocked when we put these data together,” Ayton says. To him, there’s a logic behind this, though the connections haven’t been proved. ARIA shows up on brain scans as inflammation, and generally, “it’s not controversial that neuroinflammation would lead to neurodegeneration.” It’s possible, he theorizes, that patients who develop ARIA—which tends to happen early in treatment—may later develop brain volume loss and ventricles that take on more fluid.

Last year, Eisai’s pivotal trial of lecanemab in 1795 early Alzheimer’s patients revealed that the antibody slowed the rate of cognitive decline by 27% after 18 months compared with people on a placebo. Alzheimer’s experts agreed the benefit was modest, but many celebrated the results because it’s been so difficult to find drugs that stall the devastating loss of cognition.

FDA officials who approved Eisai’s application for lecanemab noted the brain volume changes. Like the company, though, they weren’t unduly concerned. A lead FDA reviewer “questions the clinical relevance of the changes to whole brain volume and total ventricular volume,” FDA wrote in its summary review of the drug, in part because the drug met its goal of slowing cognitive decline.

But researchers say the picture could be a lot more complicated. The publicly available information on brain volume loss and increase in ventricle size are averages across a trial population, and therefore make it hard to glean whether some people have more brain changes and how they fare. As Madhav Thambisetty, a neurologist at Johns Hopkins University and chief of the clinical and translational neuroscience section at the National Institute on Aging, says, “The published results do not provide any information on whether brain volume loss and increase in ventricular volume are associated with worsening clinical and cognitive outcomes” in individual patients. The “incomplete reporting of results … is very concerning to me.”

Ayton shares the sentiment. “The lack of information increases my worry,” he says, calling on companies, including Eisai, and drug regulators to examine this issue and share additional information from the trials. “You have more data—tell us why we shouldn’t be concerned.”

FDA is planning an advisory committee meeting by July to consider whether to grant lecanemab full approval.